A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Abstract

Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2 hi CD5 + CD81 + pDC subset, distinguished by prominent dendrites and a mature phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34 + progenitors. These CD2 hi CD5 + CD81 + cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5 + CD81 + pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5 − CD81 − pDCs, human CD5 + CD81 + pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.P lasmacytoid dendritic cells (pDCs) are a distinct lineage of bone-marrow-derived cells that reside mainly in blood and lymphoid organs in the steady state, but can also be found in sites of infection, inflammation, and cancer (1). As one of the two principal lineages of dendritic cells, pDCs diverge from conventional DCs (cDCs) during maturation in the bone marrow and are recognized mainly for their rapid and massive production of type I IFN (IFNα/β) in response to viral infection (2). Although generally viewed as weak antigen-presenting cells by comparison with cDCs, pDCs interact with many types of cells, such as NK cells, cDCs, T cells, and B cells through their secretion of cytokines and chemokines in addition to type I IFN, as well as through their expression of various costimulatory molecules (3, 4). Thus, pDCs are capable of activating CD4 + helper and regulatory T cells and CD8 + cytotoxic T cells (5-16). They can also stimulate B-cell activation, differentiation into plasma cells, and antibody production through mechanisms that are not yet completely understood (17)(18)(19)(20)(21)(22).Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23-25) and humans (26-30). Surface expression of CD2 divides human pDCs into two distinct subsets. Whereas both CD2 lo and CD2 hi pDCs produce type I IFN, the CD2 hi subset secretes more IL12p40, triggers more T-cell proliferation (26), and is relatively resistant to apoptosis on the basis of higher BCL2 expression (28). Here we show that CD2 hi pDCs contain a unique subpopulation that expresses CD5 and CD81. Unlike CD2 hi CD5 − CD81 − pDCs, CD2 hi CD5 + CD81 + pDCs fail to produce type 1 IFN but ...

Human dendritic cell subsets: an update

“…A re‐interpretation of these results would suggest that in vitro culture causes short‐lived mature pDC to decline, while differentiating myeloid cDC come to dominate the preparation. This conclusion had been anticipated to a degree by a number of reports describing subsets of CD123 + pDC marked by CD2 or CD56 that show myeloid DC characteristics of inferior type I interferon production, higher interleukin‐12 (IL‐12) production and greater allo‐stimulatory capacity …”

“…Transciptional profiling has also added the markers FAM129C, CUX2 and GZMB . Several recent papers have described a small subset of CD123 + pDC that express CD2 + , CD56 + or CD5 . These cells have a distinct gene expression pattern that overlaps with myeloid cDC and are now known to contain AXL + SIGLEC 6 + myeloid pre‐cDC as described above.…”

The multiple faces of CD5

“…Recently, it has been reported that human cDC2 in tonsils, lymph nodes (LN), and blood as well as skin Langerhans and dermal DCs and blood pDCs can be further subdivided into CD5 positive and negative subpopulations, demonstrating for the first time that some human DCs express CD5 . In this context, it has been observed that CD5 is also expressed in DCs in mice (Burgueño‐Bucio et al., unpublished data).…”

“…Another study has demonstrated that skin Langerhans and dermal DCs can also be subdivided based on CD5 expression: CD5+ skin DCs are more potent at inducing CD8+ and CD4+ T cell proliferation and increased production of granzyme B, IFN‐γ, and TNF‐α in CD8+ T cells and IL‐22 in CD4+ T cells . Finally, it has also been proven that pDCs in blood can be further subdivided in CD5 positive and negative subpopulations and that CD5+ pDCs present a more mature phenotype, but that they do not produce great amounts of type I IFNs; nevertheless, they induce greater proliferation of B cells and induce plasma cell and Treg differentiation . However, the functional relevance of CD5 in these different subpopulations of DCs needs to be further investigated.…”

A type of human skin dendritic cell marked by CD5 is associated with the development of inflammatory skin disease

“…Whether the CD123 hi CD33 + C-D45RA + precursors identified in that study can be differentiated into CD5 + DCs was not tested; however, they were reported to express CD5. Two additional studies identified CD123 + DC populations in peripheral blood that are within the pDC gate and also express CD5, one that is a subset of pDC (48) and the other referred to as "AS DCs," expressing Axl and Siglec6 (49). The latter were able to transition toward the CD1c + DC state in vitro with superior capacity to activate T cells; however, the authors claim that these cells are less likely to be progenitors.…”